Respiratory syncytial virus entry and how to block it

Battles, Michael B.; McLellan, Jason S.

doi:10.1038/s41579-019-0149-x

Cited by 233 publications

(249 citation statements)

References 171 publications

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confidence: 82%

“…several key respiratory viruses ( Figure S3) (Battles and McLellan, 2019;Bochkov and 240 Gern, 2016; Laporte and Naesens, 2017; Peck et al, 2015). For examples, consistent 241 with prior findings, we found that CDHR3, a receptor for Rhinovirus C, was expressed 242 most abundantly in ciliated cells (Battles and McLellan, 2019;Bochkov and Gern, 2016;243 Laporte and Naesens, 2017; Peck et al, 2015). ANPEP, the entry receptor for HCoV-244 229E, was predominantly expressed in macrophages and to a lesser extent in club and 245 other epithelial cells (Waradon Sungnak, 2020; Yeager et al, 1992).…”

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confidence: 99%

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Single Nucleus Multiomic Profiling Reveals Age-Dynamic Regulation of Host Genes Associated with SARS-CoV-2 Infection

Wang¹,

Chiou

Poirion³

et al. 2020

Preprint

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58Respiratory failure is the leading cause of COVID-19 death and disproportionately 59 impacts adults more than children. Here, we present a large-scale snATAC-seq dataset 60 (90,980 nuclei) of the human lung, generated in parallel with snRNA-seq (46,500 nuclei), 61 from healthy donors of ~30 weeks, ~3 years and ~30 years of age. Focusing on genes 62 implicated in SARS-CoV-2 cell entry, we observed an increase in the proportion of 63 alveolar epithelial cells expressing ACE2 and TMPRSS2 in adult compared to young 64 lungs. Consistent with expression dynamics, 10 chromatin peaks linked to TMPRSS2 65 exhibited significantly increased activity with age and harbored IRF and STAT binding 66 sites. Furthermore, we identified 14 common sequence variants in age-increasing peaks 67 with predicted regulatory function, including several associated with respiratory traits and 68 TMPRSS2 expression. Our findings reveal a plausible contributor to why children are 69 more resistant to COVID-19 and provide an epigenomic basis for transferring this 70 resistance to older populations. 71 72 73 74

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supporting

confidence: 82%

mentioning

confidence: 99%

Single Nucleus Multiomic Profiling Reveals Age-Dynamic Regulation of Host Genes Associated with SARS-CoV-2 Infection

Wang¹,

Chiou

Poirion³

et al. 2020

Preprint

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“…Source file: F, fusion protein; G, glycoprotein; L, large nucleoprotein; M, matrix protein; NS, nonstructural protein; P, phosphoprotein; RSV, respiratory syncytial virus; ssRNA, single-stranded RNA (reproduced with permission). 33 adults are still less likely to have a positive result. 31 While sensitivity is greatly reduced in older patients, they remain the most sensitive detection method available.…”

Section: State Of the Art Review Box 1 Adults Are Less Likely To Testmentioning

confidence: 97%

Respiratory syncytial virus (RSV): a scourge from infancy to old age

Coultas¹,

Smyth²,

Openshaw³

2019

Thorax

112

110

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Respiratory syncytial virus (RSV) is the most common single cause of respiratory hospitalisation of infants and is the second largest cause of lower respiratory infection mortality worldwide. In adults, RSV is an under-recognised cause of deterioration in health, particularly in frail elderly persons. Infection rates typically rise in late autumn and early winter causing bronchiolitis in infants, common colds in adults and insidious respiratory illness in the elderly. Virus detection methods optimised for use in children have low detection rate in adults, highlighting the need for better diagnostic tests. There are many vaccines under development, mostly based on the surface glycoprotein F which exists in two conformations (prefusion and postfusion). Much of the neutralising antibody appears to be to the prefusion form. Vaccines being developed include live attenuated, subunit, particle based and live vectored agents. Different vaccine strategies may be appropriate for different target populations: at-risk infants, school-age children, adult caregivers and the elderly. Antiviral drugs are in clinical trial and may find a place in disease management. RSV disease is one of the major remaining common tractable challenges in infectious diseases and the era of vaccines and antivirals for RSV is on the near horizon.

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“…The initial events in RSV sensing are well-understood. After viral binding and fusion [19], RSV genomic RNA and its nucleoprotein complex including RNA-dependent RNA polymerase are released into the cytoplasm, where the polymerase produces capped and polyadenylated mRNAs encoding viral proteins in cytoplasmic inclusion bodies [20], becoming sites of viral RNA synthesis and production of innate immune responses. In epithelial cells, UV cross-linking immunoprecipitation PCR experiments have demonstrated that RSV RNA is primarily sensed by RIG-I [21].…”

Section: The Airway Epithelial Cell As a Sensor Of Rsv Replicationmentioning

confidence: 99%

RSV Reprograms the CDK9•BRD4 Chromatin Remodeling Complex to Couple Innate Inflammation to Airway Remodeling

Brasier

2020

Viruses

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Respiratory syncytial virus infection is responsible for seasonal upper and lower respiratory tract infections worldwide, causing substantial morbidity. Self-inoculation of the virus into the nasopharynx results in epithelial replication and distal spread into the lower respiratory tract. Here, respiratory syncytial virus (RSV) activates sentinel cells important in the host inflammatory response, resulting in epithelial-derived cytokine and interferon (IFN) expression resulting in neutrophilia, whose intensity is associated with disease severity. I will synthesize key findings describing how RSV replication activates intracellular NFκB and IRF signaling cascades controlling the innate immune response (IIR). Recent studies have implicated a central role for Scg1a1 + expressing progenitor cells in IIR, a cell type uniquely primed to induce neutrophilic-, T helper 2 (Th2)-polarizing-, and fibrogenic cytokines that play distinct roles in disease pathogenesis. Molecular studies have linked the positive transcriptional elongation factor-b (P-TEFb), a pleiotrophic chromatin remodeling complex in immediate-early IIR gene expression. Through intrinsic kinase activity of cyclin dependent kinase (CDK) 9 and atypical histone acetyl transferase activity of bromodomain containing protein 4 (BRD4), P-TEFb mediates transcriptional elongation of IIR genes. Unbiased proteomic studies show that the CDK9•BRD4 complex is dynamically reconfigured by the innate response and targets TGFβ-dependent fibrogenic gene networks. Chronic activation of CDK9•BRD4 mediates chromatin remodeling fibrogenic gene networks that cause epithelial mesenchymal transition (EMT). Mesenchymal transitioned epithelial cells elaborate TGFβ and IL6 that function in a paracrine manner to expand the population of subepithelial myofibroblasts. These findings may account for the long-term reduction in pulmonary function in children with severe lower respiratory tract infection (LRTI). Modifying chromatin remodeling properties of the CDK9•BRD4 coactivators may provide a mechanism for reducing post-infectious airway remodeling that are a consequence of severe RSV LRTIs.Viruses 2020, 12, 472 2 of 17 spread into the lower airways produces lower respiratory tract infection (LRTI), whose clinical features include bronchiolitis and pneumonia. Pathologically, LRTI is associated with epithelial giant cell formation, necrosis, sloughing, producing mucous plugging, ventilation-perfusion mismatching, and acute hypoxic respiratory failure [2][3][4]. The findings that the initial clinical manifestations of hypoxia are correlated with high viral titers and epithelial-derived cytokines [5,6] indicates that RSV activation of the IIR plays an important component of early disease manifestations.Observational studies of naturally occurring RSV infections in humans suggest that acute infection produces an initial neutrophilic airway inflammation [7], followed by a CD8+ T-cell response important in viral clearance (reviewed in [8]). Because protective IgA antibodies wane six months after...

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Respiratory syncytial virus entry and how to block it

Cited by 233 publications

References 171 publications

Single Nucleus Multiomic Profiling Reveals Age-Dynamic Regulation of Host Genes Associated with SARS-CoV-2 Infection

Single Nucleus Multiomic Profiling Reveals Age-Dynamic Regulation of Host Genes Associated with SARS-CoV-2 Infection

Respiratory syncytial virus (RSV): a scourge from infancy to old age

RSV Reprograms the CDK9•BRD4 Chromatin Remodeling Complex to Couple Innate Inflammation to Airway Remodeling

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